1. Field of the Invention
The present invention relates generally to the field of medicine and, more specifically, to therapeutic compositions and methods relating to Prolactin Releasing Peptide (PrRP).
2. Background Information
Epilepsy is a common condition, estimated to affect from 40 to 100 million people worldwide, and from 2 to 2.5 million Americans. Of the several clinically recognized forms of epilepsy., juvenile myoclonus epilepsy (JME) accounts for about 10% to 30% of the-cases, and childhood absence epilepsy (CAE) accounts for a further 5% to 15%. Both JME and CAE are associated with a form of seizures called xe2x80x9cgeneralized absence seizuresxe2x80x9d or xe2x80x9cpetit mal seizures.xe2x80x9d
Absence seizures are generalized non-convulsive seizures characterized by a brief period of unresponsiveness to environmental stimuli and cessation of activity, that can occur as frequently as several hundred times a day, primarily during quiet wakefulness, inattention and the transition between sleep and waking. In patients with absence seizures, generalized tonic-clonic seizures (GTCS) or xe2x80x9cgrand mal seizuresxe2x80x9d occasionally develop.
Currently available drugs to control absence seizures are often associated with adverse side effects, including gastrointestinal symptoms, tremors, sedation, temporary hair loss, dizziness, incoordination, rashes, and drug interaction complications. More seriously, potentially fatal hepatic and hematopoietic complications, as well as teratogenicity (e.g. neural tube birth defects), have been associated with absence seizure medications. Additionally, while currently available drugs are effective in many individuals, certain individuals are resistant to all known treatments.
Thus, there exists a need to identify new therapeutic agents that can be used to control absence seizures, which will significantly improve the quality of life of patients suffering from this disorder. Such drugs will likely also be effective in ameliorating conditions associated with parts of the brain responsible for absence seizures, or in diseases that share the underlying biochemical pathway of absence seizures. However, in order to rapidly screen for new drugs for controlling absence seizures, or to rationally design such drugs, it is necessary to first understand the biochemical mechanism that underlies absence seizures, and to provide appropriate assay systems for testing for new drugs. The present invention satisfies these needs and provides related advantages as well.
The invention provides a substantially pure Prolactin Releasing Peptide (PrRP) functional analog which suppresses absence seizures in a mammal, and pharmaceutical compositions containing the PrRP functional analog.
The invention also provides a method of controlling absence seizures in a mammal, by administering to a mammal susceptible to absence seizures an effective amount of PrRP or a PrRP functional analog.
Also provided are methods of identifying a compound that modulates AMPA receptor signaling in a mammal. The methods are practiced by providing a compound that is a PrRP or PrRP functional analog, and determining the ability of the compound to modulate AMPA receptor signaling.
In one method of identifying a compound that modulates AMPA receptor signaling in a mammal, a compound that is a PrRP or PrRP functional analog is provided by contacting a PrRP receptor with one or more candidate compounds under conditions wherein PrRP promotes a predetermined signal, identifying a compound that promotes production of the predetermined signal, and providing the compound. In an alternative method, a compound that is a PrRP or PrRP functional analog is provided by contacting a PrRP receptor with one or more candidate compounds under conditions wherein PrRP binds the PrRP receptor, identifying a compound that binds the PrRP receptor, and providing the compound.
In one method of identifying a compound that modulates AMPA receptor signaling in a mammal, the ability of the PrRP or PrRP functional analog to modulate AMPA receptor signaling is determined by contacting a thalamic preparation with the compound, and determining AMPA receptor mediated oscillatory activity in the preparation. In an alternative method, the ability of the PrRP or PrRP functional analog to modulate AMPA receptor signaling is determined by contacting a cell with the compound, and determining AMPA receptor mediated currents in the cell. In a further alternative method, the ability of the PrRP or PrRP functional analog to modulate AMPA receptor signaling is determined by contacting a cell with the compound, and determining AMPA receptor mediated ion influx into the cell.
Also provided are pharmaceutical compositions for controlling absence seizures in a mammal, containing a compound identified by the methods of the invention as a compound that suppresses AMPA receptor signaling. Further provided are methods of controlling absence seizures in a mammal by administering to a mammal susceptible to absence seizures an effective amount of such pharmaceutical compositions.
The invention also provides methods of identifying a compound for controlling absence seizures in a mammal. The methods are practiced by providing a compound that is a PrRP or PrRP functional analog, and determining the ability of the compound to control absence seizures in a mammal.
In one method of identifying a compound for controlling absence seizures in a mammal, a compound that is a PrRP or PrRP functional analog is provided by contacting a PrRP receptor with one or more candidate compounds under conditions wherein PrRP promotes a predetermined signal, identifying a compound that promotes production of the predetermined signal, and providing the compound. In an alternative method, a compound that is a PrRP or PrRP functional analog is provided by contacting a PrRP receptor with one or more candidate compounds under conditions wherein PrRP binds the PrRP receptor, identifying a compound that binds the PrRP receptor, and providing the compound.
In one method of identifying a compound for controlling absence seizures in a mammal, the ability of the PrRP or PrRP functional analog to control absence seizures is practiced by administering the compound to a mammal susceptible to absence seizures, and determining seizure activity in the mammal.
Also provided are pharmaceutical compositions for controlling absence seizures in a mammal, containing a compound identified by the methods of the invention as a compound for controlling absence seizures. Further provided are methods of controlling absence seizures in a mammal by administering to a mammal susceptible to absence seizures an effective amount of such pharmaceutical compositions.